Controlled delivery of beneficial agents such as drugs in the medical and veterinary fields has been accomplished by a variety of methods that may employ various types of drug delivery device. A range of exemplary devices and methods are well described in “Encyclopedia of Controlled Drug Delivery” 1999, published by John Wiley & Sons Inc, edited by Edith Mathiowitz. Drug delivery devices including an implantable device, which device can be based on, for example, diffusive, erodible or convective systems, e.g., pumps, such as osmotic pumps, that may or may not be connected to a catheter, biodegradable implants, electrodiffusion systems, electroosmosis systems, vapor pressure pumps, electrolytic pumps, effervescent pumps, piezoelectric pumps, electrochemical pumps, erosion-based systems, electromechanical systems, liposomes, depots, or microspheres. Every containerized device requires an orifice of one sort or another, and such an orifice must address the particular needs of drug delivery in a certain situation, such as the need for low flow rate, steady, predictable flow rate and the need to keep the orifice closed until flow is required.
One approach for delivering a beneficial agent involves the use of implantable diffusional systems. For example, subdermal implants for contraception are descried by Philip D. Darney in Current Opinion in Obstetrics and Gynecology, 1991, 3:470-476. Norplant® requires the placement of 6 levonorgestrel-filled silastic capsules under the skin. Protection from conception for up to 5 years is achieved. The implants operate by simple diffusion, that is, the active agent diffuses through the polymeric material at a rate that is controlled by the characteristics of the active agent formulation and the polymeric material.
Another method for controlled prolonged delivery of a beneficial agent involves the use of an implantable osmotic delivery system. Osmotic delivery systems are very reliable in delivering the beneficial agent over an extended period of time. The osmotic pressure generated by an osmotic pump also produces a delivery rate of the beneficial agent into the body which is relatively constant as compared with other types of delivery systems.
In general, osmotic delivery systems operate by imbibing fluid from the outside environment and releasing corresponding amounts of the beneficial agent Osmotic delivery systems, commonly referred to as “osmotic pumps”, generally include some type of a capsule having walls which selectively pass water into an interior of the capsule which contains a water-attracting agent. The absorption of water by the water-attracting agent within the capsule reservoir creates an osmotic pressure within the capsule which causes the beneficial agent to be delivered from the capsule. The water-attracting agent may be the beneficial agent delivered to the patient, however, in most cases, a separate agent is used specifically for its ability to draw water into the capsule.
When a separate osmotic agent is used, the osmotic agent may be separated from the beneficial agent within the capsule by a movable dividing member or piston. The structure of the capsule is such that the capsule does not expand when the osmotic agent takes in water. As the osmotic agent expands, it causes the movable dividing member or piston to move, which in turn causes the beneficial agent to be discharged through an orifice at the same volumetric rate that water enters the osmotic agent by osmosis.
Another method for controlled prolonged delivery of a beneficial agent involves the use of an implantable chemical or electrochemical delivery system. A controlled delivery device for holding and administering a biologically active agent includes a housing which encloses a displacing member, a chemical or electrochemical cell that generates pressure, and may include activation and control circuitry. The electrochemical or chemical cell generates gas within the housing, forcing the displacing member against the beneficial agents contained within the housing and forcing the beneficial agents through an outlet port and into the environment of use at a predetermined rate.
The orifice in any of the above devices controls the interaction of the beneficial agent with the external fluid environment. The orifice serves the important function of isolating the beneficial agent from the external fluid environment, since any contamination of the beneficial agent by external fluids may adversely affect the utility of the beneficial agent. For example, the inward flux of materials of the external fluid environment due to diffusion or osmosis may contaminate the interior of the capsule, destabilizing, diluting, or otherwise altering the beneficial agent formulation. Another important function of the orifice is to control or limit diffusional flow of the beneficial agent through the orifice into the external fluid environment.
In known delivery devices, these functions have typically been performed by flow moderators. A flow moderator may consist of a tubular passage having a particular cross sectional area and length. The cross sectional area and length of the flow moderator is chosen such that the average linear velocity of the exiting beneficial agent is higher than that of the linear inward flux of materials in the external environment due to diffusion or osmosis, thereby attenuating or moderating back diffusion and its deleterious effects of contaminating the interior of the osmotic or diffusion pump.
In addition, the dimensions of the flow moderator may be chosen such that the diffusive flux of the beneficial agent out of the orifice is small in comparison to the convective flux. One problem with flow moderators, however, is that the passage may become clogged or obstructed with particles suspended in the beneficial agent or in fluid from the external environment. Such clogging may be reduced or eliminated by increasing the diameter of the passage to 5 mil or more, for example. However, this increase results in a greater rate of diffusion of the beneficial agent out of the pump. A corresponding increase also occurs in the back diffusion of the external fluid into the pump which may contaminate the beneficial agent and adversely affect the desired delivery rate of the beneficial agent. Tolerances during fabrication also frequently dictate that the orifice diameter be greater than about 5 mils.
Systems with a long straight flow moderator are also impractical for implantation applications because they increase the size of the implant significantly making the system difficult to implant.
Leakage of the beneficial agent from the pump or device, prior to implanting the same, may occur due to pressure changes in the reservoir containing the beneficial agent caused by changes in temperature of the environment that the pump is being stored in. Loss of beneficial agent to the environment through evaporation is another common occurrence to varying degrees during the storage or shelf life of various implantable pumps.
Another problem associated with pressure driven implantable drug delivery devices is known as the burst effect, wherein, due to thermal expansion of a drug or other beneficial agent upon removing the implantable device from a room temperature, shelf environment and implanting it into an environment at body temperature, an initial volume or bolus of the drug or beneficial agent is delivered from the device which is often much larger than a predetermined measured dose called for. This phenomenon can be a critical problem, causing severe damage or even death to the patient in the worst scenarios.
Current flow modulators also cause separation of beneficial agents which contain suspensions of bioactive macromolecules (proteins, genes, etc.). When such suspensions pass along a restriction in current flow modulators, the suspension separates and the delivery concentration of bioactive macromolecules varies.
Additionally, if a drug formulation is allowed to sit in a delivery outlet channel during storage, then precipitation of solutes out of solution (due to evaporation and surface effects) may cause the delivery outlet channel to become blocked with precipitated solute.
The above problems are particularly acute when the drug to be delivered is highly potent, when the volume to be delivered is small, and when delivery is done aver a prolonged period of time.
Thus, there is a need for methods and devices that solve the problems of keeping the system closed until needed, controlling drug burst due to differential thermal expansion of the drug and the container, reducing precipitation of drug causing blockage of the outflow channel, and providing a uniform, even and predictable flow of drug out of the drug delivery device. The current invention fulfills these needs.